Background: Patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy (RT) or chemoradiation (CRT) may become immunocompromised. In this population-based study, we aimed to investigate the risk factors, microbiological aetiologies, prognosis and impact on early non-cancer mortality of bloodstream infections (BSIs) after RT/CRT. Methods: Patients with HNSCC of the pharynx, larynx and oral cavity treated with curative-intent RT/CRT in Denmark between 2010 and 2017 and subsequent BSI episodes occurring within 18 months of RT/CRT initiation were identified in national registries. Results: We included 5674 patients and observed 238 BSIs. Increasing age, stage and performance status were significantly associated with an elevated BSI risk, while sex, smoking and high-grade mucositis were not. Human papillomavirus-positive oropharyngeal cancer patients had a decreased risk. Staphylococcus aureus accounted for 34% of episodes occurring during the first 3 months. The 30-day post-BSI mortality rate was 26% (95% confidence interval: 19–32) and BSIs were involved in 10% of early non-cancer deaths. Conclusion: The risk of BSI development is associated with several patient- and disease-related factors and BSIs contribute considerably to early non-cancer mortality. Empiric antibiotic treatment regimens should prioritise coverage for S. aureus when treating suspected systemic infection in this population.